The regenerative capacity of airway epithelium in response to injury is critical for lung recovery from environmental insults and preventing the progression of respiratory diseases. So it is important to understand how epithelial regeneration is regulated to potentially enhance recovery and reduce lung injury. MicroRNAs and Hippo pathway have emerged as key modulators of both organ development and adult tissue repair and regeneration. We recently demonstrated that the microRNA cluster, miR302-367, promotes a high level of cell proliferation but less differentiated phenotype in the developing lung and heart. Overexpression of miR302-367 in adult heart promotes cardiomyocyte proliferation and cardiac regeneration. MiR302-367 functions, in part, by targeting several components of the Hippo signaling pathway, which negatively regulates the activity of Yap and Taz. Yap and Taz are key transcriptional co-activators that drive the expression of their downstream targets to promote cell proliferation and inhibit cell death. We have explored the mechanisms that regulate alveolar epithelial repair and regeneration in adult lung following injury induced by bacterial pneumonia. Bacterial pneumonia remains a leading cause of mortality in children and the elderly. While extensive studies have focused on bacterial virulence and host immune responses, little is known about the type lung injury induced by bacterial pneumonia and their subsequent regeneration and repair. We show that mice with infection of Streptococcus pneumoniae (Sp) have markedly injuries in the lung parenchyma followed by visible repair and regeneration. In response to Sp-induced injury, pre-existing SPC-expressing epithelial type II cells in the alveolus function as epithelial progenitor cells. They proliferate and differentiate ito type I cell at the sites of affected alveolar region. Notably, the expression of miR302-367 and Yap/Taz target, Cysteine rich protein 61, is increased in distal lung epithelium. Overexpression of miRNA302-367 in SPC- expressing cells enhanced alveolar epithelial repair and regeneration. Administration of small molecule miR302-mimics in mice with bacterial pneumonia promoted distal airway epithelial regeneration, enhanced mouse recovery and survival. Based on these preliminary studies, we hypothesize that miR302-367 and Hippo pathway regulate lung epithelial gene transcription to promote epithelial repair and regeneration. Targeting microRNA-Hippo pathway may represent a novel therapeutic approach to promote recovery from injury induced by bacterial pneumonia. This project aims to define the mechanistic role of miR302-367 and Hippo signaling in distal airway epithelial repair and regeneration by (1) modulating miR302-367 and Yap/Taz expression in alveolar epithelial progenitor cells in murine model system, and (2) by defining the interactions of miR302-367 and Hippo signaling in governing gene network that control alveolar epithelial repair and regeneration, and (3) by examining the therapeutic potentials of miR-mimics and inhibiting Hippo pathway in recovery from bacteria-induced injury.
The regenerative capacity of alveolar epithelium in response to injury is critical for lung recovery from environmental insults and preventing the progression o respiratory diseases. We hypothesize that promoting airway epithelial repair and regeneration by modulating distal lung epithelial progenitor cell activity with microRNA-Hippo pathway can promote recovery from injury induced by bacterial pneumonia. We will test this hypothesis and in doing so we hope to develop a novel therapeutic strategy directed at promoting lung epithelial repair and regeneration and recovery from bacteria-induced lung injury
| Shanmughapriya, Santhanam; Tomar, Dhanendra; Dong, Zhiwei et al. (2018) FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation. Nat Commun 9:3449 |
